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Biology subjects

Karl W Broman

Publications and source records attributed to Karl W Broman.

3 recordsLinked to original sources

Mapping quantitative trait loci underlying function-valued traits using functional principal component analysis and multi-trait mapping

We previously proposed a simple regression-based method to map quantitative trait loci underlying function-valued phenotypes. In order to better handle the case of noisy phenotype measurements and accommodate the correlation structure among time points, we propose an alternative approach that maintains much of the simplicity and speed of the regression-based method. We overcome noisy measurements by replacing the observed data with a smooth approximation. We then apply functional principal component analysis, replacing the smoothed phenotype data with a small number of principal components. Quantitative trait locus mapping is applied to these dimension-reduced data, either with a multi-trait method or by considering the traits individually and then taking the average or maximum LOD score across traits. We apply these approaches to root gravitropism data on Arabidopsis recombinant inbred lines and further investigate their performance in computer simulations. Our methods have been implemented in the R package, funqtl.

Genetics

Identification of Slco1a6 as a candidate gene that broadly affects gene expression in mouse pancreatic islets

We surveyed gene expression in six tissues in an F2 intercross between mouse strains C57BL/6J (abbreviated B6) and BTBR T+ tf /J (abbreviated BTBR) made genetically obese with the Leptin(ob) mutation. We identified a number of expression quantitative trait loci (eQTL) affecting the expression of numerous genes distal to the locus, called trans-eQTL hotspots. Some of these trans-eQTL hotspots showed effects in multiple tissues, whereas some were specific to a single tissue. An unusually large number of transcripts (7% of genes) mapped in trans to a hotspot on chromosome 6, specifically in pancreatic islets. By considering the first two principal components of the expression of genes mapping to this region, we were able to convert the multivariate phenotype into a simple Mendelian trait. Fine-mapping the locus by traditional methods reduced the QTL interval to a 298 kb region containing only three genes, including Slco1a6, one member of a large family of organic anion transporters. Direct genomic sequencing of all Slco1a6 exons identified a non-synonymous coding SNP that converts a highly conserved proline residue at amino acid position 564 to serine. Molecular modeling suggests that Pro564 faces an aqueous pore within this 12-transmembrane domain-spanning protein. When transiently overexpressed in HEK293 cells, BTBR OATP1A6-mediated cellular uptake of the bile acid taurocholic acid (TCA) was enhanced compared to B6 OATP1A6. Our results suggest that genetic variation in Slco1a6 leads to altered transport of TCA (and potentially other bile acids) by pancreatic islets, resulting in broad gene regulation.

Genetics

R/qtlcharts: interactive graphics for quantitative trait locus mapping

Every data visualization can be improved with some level of interactivity. Interactive graphics hold particular promise for the exploration of high-dimensional data. R/qtlcharts is an R package to create interactive graphics for experiments to map quantitative trait loci (QTL; genetic loci that influence quantitative traits). R/qtlcharts serves as a companion to the R/qtl package, providing interactive versions of R/qtls static graphs, as well as additional interactive graphs for the exploration of high-dimensional genotype and phenotype data.

Genetics